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Clinical Trial Results:
A PHASE 2B, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ONCE-DAILY ORALLY ADMINISTERED PH-797804 FOR 12 WEEKS IN ADULTS WITH MODERATE TO SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ON A BACKGROUND OF TIOTROPIUM BROMIDE

Summary
EudraCT number	2011-005864-11
Trial protocol	CZ HU SE PL SK ES BG DE
Global end of trial date	18 Sep 2013

Results information
Results version number	v1(current)
This version publication date	08 Jul 2016
First version publication date	11 Jul 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

A6631033

ISRCTN number

US NCT number

NCT01543919

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017, New York, United States, 10017

Public contact

Clinical Trials.gov Call Center, Pfizer Inc, 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Clinical Trials.gov Call Center, Pfizer Inc, 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

18 Sep 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Sep 2013

Global end of trial reached?

Yes

Global end of trial date

18 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

To characterize the dose response relationship of PH-797804 on change from baseline in trough (pre-treatment and pre-bronchodilator) FEV1 at Week 12 compared to placebo in COPD patients on a background of tiotropium.

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed; in particular, those affording greater protection to the safety of study subjects.

Background therapy

Tiotropium bromide 18 microgram (mcg) once daily

Evidence for comparator

Actual start date of recruitment

13 Apr 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 15

Country: Number of subjects enrolled

Slovakia: 94

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Sweden: 44

Country: Number of subjects enrolled

Bulgaria: 60

Country: Number of subjects enrolled

Czech Republic: 82

Country: Number of subjects enrolled

Germany: 68

Country: Number of subjects enrolled

Hungary: 99

Country: Number of subjects enrolled

Argentina: 12

Country: Number of subjects enrolled

Canada: 39

Country: Number of subjects enrolled

Japan: 42

Country: Number of subjects enrolled

South Africa: 30

Country: Number of subjects enrolled

Taiwan: 2

Country: Number of subjects enrolled

United States: 121

Worldwide total number of subjects

721

EEA total number of subjects

475

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

385

From 65 to 84 years

336

85 years and over

Subject disposition

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Recruitment details

Screening details

The study was conducted in 14 countries (Canada, United States, South Africa, Hungary, Argentina, Bulgaria, Czech Republic, Germany, Japan, Poland, Slovakia, Spain, Sweden, and Taiwan). Male or female subjects of 40 to 80 years inclusive, with a diagnosis, for at least 6 months, of moderate to severe COPD (GOLD) were enrolled.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Blinding implementation details

The study adopted a double-blind design to preserve the blinding. A double dummy system was utilized in order to maintain the blind.

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received placebo matched to PH-797804 tablet plus tiotropium bromide 18 microgram (mcg) orally once daily for 12 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablets matching the different doses of PH-797804 plus tiotropium bromide were administered orally once per day in the morning for 12 weeks.

PH-797804 0.25 mg

Arm description

Subjects received PH-797804 0.25 milligram (mg) plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

PH-797804 0.25 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PH-797804 0.25 mg plus tiotropium bromide was administered orally once per day in the morning for 12 weeks.

PH-797804 1 mg

Arm description

Subjects received PH-797804 1 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

PH-797804

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PH-797804 1 mg plus tiotropium bromide was administered orally once per day in the morning for 12 weeks.

PH-797804 3 mg

Arm description

Subjects received PH-797804 3 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

PH-797804

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PH-797804 3 mg plus tiotropium bromide was administered orally once per day in the morning for 12 weeks.

PH-797804 6 mg

Arm description

Subjects received PH-797804 6 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

PH-797804

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PH-797804 6 mg plus tiotropium bromide was administered orally once per day in the morning for 12 weeks.

PH-797804 10 mg

Arm description

Subjects received PH-797804 10 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Arm type

Experimental

Investigational medicinal product name

PH-797804

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PH-797804 10 mg plus tiotropium bromide was administered orally once per day in the morning for 12 weeks.

Number of subjects in period 1	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Started	181	90	91	88	182	89
Treated/Baseline	181	90	91	88	182	89
Completed	162	79	76	75	153	70
Not completed	19	11	15	13	29	19
Adverse event, serious fatal	2	-	-	-	2	-
Consent withdrawn by subject	2	1	2	1	4	1
Did not meet entrance criteria	4	1	1	1	2	3
Adverse event, non-fatal	9	8	7	11	19	14
Unspecified	1	1	3	-	-	1
Insufficient clinical response	1	-	1	-	-	-
Protocol deviation	-	-	1	-	2	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to PH-797804 tablet plus tiotropium bromide 18 microgram (mcg) orally once daily for 12 weeks.

Reporting group title

PH-797804 0.25 mg

Reporting group description

Subjects received PH-797804 0.25 milligram (mg) plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 1 mg

Reporting group description

Subjects received PH-797804 1 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 3 mg

Reporting group description

Subjects received PH-797804 3 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 6 mg

Reporting group description

Subjects received PH-797804 6 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 10 mg

Reporting group description

Subjects received PH-797804 10 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group values	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg	Total
Number of subjects	181	90	91	88	182	89	721
Age categorical
Units: Subjects
18 to 44 years	1	0	1	0	2	1	5
45 to 64 years	103	52	51	49	92	33	380
Greater than or equal to (>=) 65 years	77	38	39	39	88	55	336
Gender categorical
Units: Subjects
Female	60	33	38	33	67	37	268
Male	121	57	53	55	115	52	453

End points

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Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to PH-797804 tablet plus tiotropium bromide 18 microgram (mcg) orally once daily for 12 weeks.

Reporting group title

PH-797804 0.25 mg

Reporting group description

Subjects received PH-797804 0.25 milligram (mg) plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 1 mg

Reporting group description

Subjects received PH-797804 1 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 3 mg

Reporting group description

Subjects received PH-797804 3 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 6 mg

Reporting group description

Subjects received PH-797804 6 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 10 mg

Reporting group description

Subjects received PH-797804 10 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Primary: Placebo-corrected change from baseline in trough (pre-treatment and pre-bronchodilator) FEV1 at Week 12

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End point title

Placebo-corrected change from baseline in trough (pre-treatment and pre-bronchodilator) FEV1 at Week 12 ^[1] ^[2]

End point description

Forced expiratory volume in 1 second (FEV1) is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Trough FEV1 was obtained from spirometry, performed before study treatment administration. The primary objective of the study was to characterize the dose-response relationship of PH-797804 on change from baseline in trough (pre-treatment and pre-bronchodilator) FEV1 at Week 12 compared to placebo in subjects with COPD on a background of tiotropium. The dose-response relationship of change from baseline trough FEV1 at Week 12 was modeled using a Bayesian maximum possible effect (Emax) model. Placebo-adjusted data was reported. Analysis was done on the Per-Protocol Analysis Set (PPAS) which consisted of all subjects who had no major protocol violations and produced valid trough FEV1 readings at both baseline and the Week 12 visit.

End point type

Primary

End point timeframe

Baseline and Week 12

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: A Bayesian maximum possible effect (Emax) model with weakly informative priors was employed to test if any of the doses were efficacious compared to placebo based on predefined decision criteria. However, none of the 5 doses of PH-797804 met the predefined decision criteria for improvement over placebo in change from baseline trough FEV1 at Week 12.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-corrected estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	88	86	86	172	85
Units: Liter (L)
number (confidence interval 95%)	0.0316 (0.00209 to 0.0717)	0.0472 (0.00703 to 0.0877)	0.0554 (0.0145 to 0.0949)	0.0587 (0.0184 to 0.0982)	0.0604 (0.0202 to 0.0999)

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator FEV1 at Weeks 2, 6, and 10

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End point title

Placebo-adjusted change from baseline in trough, pre-bronchodilator FEV1 at Weeks 2, 6, and 10 ^[3]

End point description

FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Trough FEV1 was obtained from spirometry, performed before study treatment administration. The change from baseline in trough, pre-bronchodilator FEV1 at Weeks 2, 6, and 10 was analyzed using a longitudinal mixed effects model with treatment, week and treatment-by-week interaction fitted as factors, and the baseline value as a covariate. Placebo-adjusted data was reported. Analysis was done on the Full Analysis Set (FAS) which included all randomized subjects, who had at least 1 valid FEV1 measurement during the active double-blind phase of the study. "n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, and 10

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[4]	88 ^[5]	86 ^[6]	175 ^[7]	88 ^[8]
Units: Liter (L)
arithmetic mean (standard error)
Week 2 (n=88, 82, 83, 171, 84)	0.0488 ( 0.0197 )	0.0723 ( 0.0201 )	0.0658 ( 0.0201 )	0.0695 ( 0.0162 )	0.0567 ( 0.02 )
Week 6 (n=84, 78, 78, 158, 78)	0.0469 ( 0.241 )	0.0648 ( 0.0247 )	0.0301 ( 0.0247 )	0.0532 ( 0.02 )	0.0668 ( 0.0247 )
Week 10 (n=80, 74, 77, 147, 70)	0.0501 ( 0.0261 )	0.0612 ( 0.0267 )	0.0225 ( 0.0265 )	0.0503 ( 0.0217 )	0.0355 ( 0.027 )

Notes
[4] - Subjects who were evaluable for this measure.
[5] - Subjects who were evaluable for this measure.
[6] - Subjects who were evaluable for this measure.
[7] - Subjects who were evaluable for this measure.
[8] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator forced expiratory volume in 6 seconds (FEV6) at Weeks 2, 6, 10 and 12

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End point title

Placebo-adjusted change from baseline in trough, pre-bronchodilator forced expiratory volume in 6 seconds (FEV6) at Weeks 2, 6, 10 and 12 ^[9]

End point description

FEV6 is the maximal volume of air exhaled in the first 6 seconds of a forced expiration from a position of full inspiration. Trough FEV6 was obtained from spirometry, performed before study treatment administration. The change from baseline in trough, pre-bronchodilator FEV6 at Weeks 2, 6, 10 and 12 was analyzed using a longitudinal mixed effects model with treatment, week and treatment-by-week interaction fitted as factors, and the baseline value as a covariate. Placebo-adjusted data was reported. Analysis was done on the FAS population which included all randomized subjects, who had at least 1 valid FEV1 measurement during the active double-blind phase of the study. "n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[10]	88 ^[11]	86 ^[12]	175 ^[13]	88 ^[14]
Units: Liter (L)
arithmetic mean (standard error)
Week 2 (n=88, 82, 83, 171, 84)	0.0523 ( 0.0266 )	0.0806 ( 0.0272 )	0.0439 ( 0.0271 )	0.0707 ( 0.0219 )	0.0558 ( 0.027 )
Week 6 (n=84, 78, 78, 158, 78)	0.0643 ( 0.0338 )	0.075 ( 0.0346 )	-0.0003 ( 0.0345 )	0.0365 ( 0.028 )	0.0817 ( 0.0346 )
Week 10 (n=80, 74, 77, 147, 70)	0.0591 ( 0.0337 )	0.0556 ( 0.0346 )	-0.0037 ( 0.0343 )	0.0427 ( 0.0281 )	0.0366 ( 0.035 )
Week 12 (n=78, 73, 73, 146, 69)	0.0351 ( 0.036 )	0.1132 ( 0.0368 )	0.0119 ( 0.0367 )	0.0367 ( 0.0298 )	0.0347 ( 0.0373 )

Notes
[10] - Subjects who were evaluable for this measure.
[11] - Subjects who were evaluable for this measure.
[12] - Subjects who were evaluable for this measure.
[13] - Subjects who were evaluable for this measure.
[14] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator forced vital capacity (FVC) at Weeks 2, 6, 10 and 12

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End point title

Placebo-adjusted change from baseline in trough, pre-bronchodilator forced vital capacity (FVC) at Weeks 2, 6, 10 and 12 ^[15]

End point description

FVC is the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Trough FVC was obtained from spirometry, performed before study treatment administration. The change from baseline in trough, pre-bronchodilator FVC at Weeks 2, 6, 10 and 12 was analyzed using a longitudinal mixed effects model with treatment, week and treatment-by-week interaction fitted as factors, and the baseline value as a covariate. Placebo-adjusted data was reported. Analysis was done on the FAS population which included all randomized subjects, who had at least 1 valid FEV1 measurement during the active double-blind phase of the study."n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[16]	88 ^[17]	86 ^[18]	175 ^[19]	88 ^[20]
Units: litre(s)
arithmetic mean (standard error)
Week 2 (n=88, 82, 83, 171, 84)	0.0595 ( 0.032 )	0.058 ( 0.0328 )	0.0054 ( 0.0327 )	0.0686 ( 0.0264 )	0.0447 ( 0.0326 )
Week 6 (n=84, 78, 78, 158, 78)	0.0647 ( 0.0419 )	0.0511 ( 0.043 )	-0.0401 ( 0.0429 )	0.003 ( 0.0348 )	0.0665 ( 0.043 )
Week 10 (n=80, 74, 77, 147, 70)	0.0479 ( 0.0406 )	0.0398 ( 0.0416 )	-0.0575 ( 0.0412 )	0.0153 ( 0.0338 )	0.0235 ( 0.0421 )
Week 12 (n=78, 73, 73, 146, 69)	0.0214 ( 0.0431 )	0.0907 ( 0.0441 )	-0.0295 ( 0.044 )	0.0026 ( 0.0357 )	0.0295 ( 0.0446 )

Notes
[16] - Subjects who were evaluable for this measure.
[17] - Subjects who were evaluable for this measure.
[18] - Subjects who were evaluable for this measure.
[19] - Subjects who were evaluable for this measure.
[20] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator inspiratory capacity (IC) at Weeks 2, 6, 10 and 12

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End point title

Placebo-adjusted change from baseline in trough, pre-bronchodilator inspiratory capacity (IC) at Weeks 2, 6, 10 and 12 ^[21]

End point description

IC is the maximum volume of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Trough IC was obtained from spirometry, performed before study treatment administration. The change from baseline in trough, pre-bronchodilator IC at Weeks 2, 6, 10 and 12 was analyzed using a longitudinal mixed effects model with treatment, week and treatment-by-week interaction fitted as factors, and the baseline value as a covariate. Placebo-adjusted data was reported. Analysis was done on the FAS which included all randomized subjects, who had at least 1 valid FEV1 measurement during the active double-blind phase of the study. "n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[22]	88 ^[23]	86 ^[24]	175 ^[25]	88 ^[26]
Units: litre(s)
arithmetic mean (standard error)
Week 2 (n=88, 83, 83, 171, 85)	0.0151 ( 0.0384 )	0.0596 ( 0.0392 )	0.0905 ( 0.0392 )	0.0704 ( 0.0316 )	0.0762 ( 0.0389 )
Week 6 (n=84, 78, 78, 158, 77)	0.0758 ( 0.0422 )	0.0721 ( 0.0433 )	0.0277 ( 0.0432 )	0.0607 ( 0.035 )	0.0428 ( 0.0433 )
Week 10 (n=80, 74, 77, 147, 70)	-0.0065 ( 0.0437 )	0.0133 ( 0.0449 )	0.0202 ( 0.0444 )	0.0099 ( 0.0364 )	0.0429 ( 0.0455 )
Week 12 (n=78, 73, 73, 146, 69)	-0.0671 ( 0.0441 )	0.0745 ( 0.0451 )	0.0661 ( 0.0451 )	0.0179 ( 0.0366 )	0.0419 ( 0.0457 )

Notes
[22] - Subjects who were evaluable for this measure.
[23] - Subjects who were evaluable for this measure.
[24] - Subjects who were evaluable for this measure.
[25] - Subjects who were evaluable for this measure.
[26] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Average placebo-adjusted change from baseline in trough, pre-bronchodilator FEV1, FEV6, FVC, and IC over 12 weeks of treatment

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End point title

Average placebo-adjusted change from baseline in trough, pre-bronchodilator FEV1, FEV6, FVC, and IC over 12 weeks of treatment ^[27]

End point description

FEV1=the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration; FEV6=the maximal volume of air exhaled in the first 6 seconds of a forced expiration from a position of full inspiration; FVC=the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible; IC=the maximum volume of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Trough FEV1, FEV6, FVC, and IC were obtained from spirometry, performed before study treatment administration. The average change from baseline in trough, pre-bronchodilator FEV1, FEV6, FVC, and IC over 12 weeks of treatment was analyzed using a longitudinal mixed effects model with treatment, week and treatment-by-week interaction fitted as factors, and the baseline value as a covariate. Placebo-adjusted data was reported. "n" signifies subjects with available data for each arm respectively. FAS used.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[28]	88 ^[29]	86 ^[30]	175 ^[31]	88 ^[32]
Units: litre(s)
arithmetic mean (standard error)
FEV1 (n=88, 83, 83, 172, 84)	0.0455 ( 0.0194 )	0.0745 ( 0.0198 )	0.0397 ( 0.0198 )	0.0563 ( 0.0161 )	0.052 ( 0.0199 )
FEV6 (n=88,83, 83, 172, 84)	0.0527 ( 0.0259 )	0.0811 ( 0.0265 )	0.013 ( 0.0264 )	0.0467 ( 0.0214 )	0.0522 ( 0.0266 )
FVC (n=88, 83, 83, 172, 84)	0.0484 ( 0.0318 )	0.0599 ( 0.0325 )	-0.0304 ( 0.0324 )	0.0224 ( 0.0263 )	0.041 ( 0.0326 )
IC (n=88, 83, 83, 172, 85)	0.0043 ( 0.0327 )	0.0549 ( 0.0334 )	0.0511 ( 0.0333 )	0.0397 ( 0.0271 )	0.0509 ( 0.0335 )

Notes
[28] - Subjects who were evaluable for this measure.
[29] - Subjects who were evaluable for this measure.
[30] - Subjects who were evaluable for this measure.
[31] - Subjects who were evaluable for this measure.
[32] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FEV1 at Weeks 0 and 12

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End point title

Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FEV1 at Weeks 0 and 12 ^[33]

End point description

FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Trough FEV1 was obtained from spirometry, performed before study treatment administration. The change from baseline in post-study drug, pre-bronchodilator FEV1 at Weeks 0 and 12 was analyzed using the analyis of covariance (ANCOVA) model with treatment as a fixed effect and baseline value as a covariate. Post-study drug spirometry was performed 15-30 minutes after administration of study drug at the Weeks 0 and 12 visits. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at the specified time point for each arm respectively.

End point type

Secondary

End point timeframe

Week 0 (randomization) and Week 12.

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[34]	88 ^[35]	86 ^[36]	175 ^[37]	88 ^[38]
Units: litre(s)
arithmetic mean (standard error)
Week 0 (n=89, 85, 85, 175, 87)	0.0026 ( 0.013 )	-0.0011 ( 0.0132 )	0.0052 ( 0.0132 )	0.0128 ( 0.0107 )	-0.0019 ( 0.0131 )
Week 12 (n=77, 72, 72, 146, 69)	-0.011 ( 0.0116 )	-0.0121 ( 0.0119 )	-0.0137 ( 0.0119 )	-0.0064 ( 0.0096 )	0.0045 ( 0.0121 )

Notes
[34] - Subjects who were evaluable for this measure.
[35] - Subjects who were evaluable for this measure.
[36] - Subjects who were evaluable for this measure.
[37] - Subjects who were evaluable for this measure.
[38] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FEV6 at Weeks 0 and 12

Top of page

End point title

Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FEV6 at Weeks 0 and 12 ^[39]

End point description

FEV6 is the maximal volume of air exhaled in the first 6 seconds of a forced expiration from a position of full inspiration. Trough FEV6 was obtained from spirometry, performed before study treatment administration. The change from baseline in post-study drug, pre-bronchodilator FEV6 at Weeks 0 and 12 was analyzed using the ANCOVA model with treatment as a fixed effect and baseline value as a covariate. Post-study drug spirometry was performed 15-30 minutes after administration of study drug at the Weeks 0 and 12 visits. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at the specified time point for each arm respectively.

End point type

Secondary

End point timeframe

Week 0 (randomization) and Week 12.

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[40]	88 ^[41]	86 ^[42]	175 ^[43]	88 ^[44]
Units: litre(s)
arithmetic mean (standard error)
Week 0 (n=89, 85, 85, 175, 87)	0.0239 ( 0.0188 )	0.0046 ( 0.0192 )	-0.0061 ( 0.0191 )	0.0176 ( 0.0155 )	0.0009 ( 0.019 )
Week 12 (n=77, 72, 72, 146, 69)	-0.0163 ( 0.0168 )	-0.0095 ( 0.0172 )	-0.0226 ( 0.0172 )	-0.0115 ( 0.0139 )	-0.0095 ( 0.0175 )

Notes
[40] - Subjects who were evaluable for this measure.
[41] - Subjects who were evaluable for this measure.
[42] - Subjects who were evaluable for this measure.
[43] - Subjects who were evaluable for this measure.
[44] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator IC at Weeks 0 and 12

Top of page

End point title

Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator IC at Weeks 0 and 12 ^[45]

End point description

IC is the maximum volume of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Trough IC was obtained from spirometry, performed before study treatment administration. The change from baseline in post-study drug, pre-bronchodilator IC at Weeks 0 and 12 was analyzed using the ANCOVA model with treatment as a fixed effect and baseline value as a covariate. Post-study drug spirometry was performed 15-30 minutes after administration of study drug at the Weeks 0 and 12 visits. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at the specified time point for each arm respectively.

End point type

Secondary

End point timeframe

Week 0 (randomization) and Week 12.

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[46]	88 ^[47]	86 ^[48]	175 ^[49]	88 ^[50]
Units: litre(s)
arithmetic mean (standard error)
Week 0 (n=89, 85, 85, 175, 87)	-0.0577 ( 0.0353 )	-0.1135 ( 0.0358 )	-0.0957 ( 0.0358 )	-0.0768 ( 0.029 )	-0.0759 ( 0.0356 )
Week 12 (n=77, 72, 73, 146, 69)	0.0555 ( 0.0321 )	0.0092 ( 0.0328 )	-0.0075 ( 0.0327 )	0.0203 ( 0.0265 )	-0.0116 ( 0.0333 )

Notes
[46] - Subjects who were evaluable for this measure.
[47] - Subjects who were evaluable for this measure.
[48] - Subjects who were evaluable for this measure.
[49] - Subjects who were evaluable for this measure.
[50] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FEV1 at Weeks 0 and 12

Top of page

End point title

Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FEV1 at Weeks 0 and 12 ^[51]

End point description

FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Trough FEV1 was obtained from spirometry, performed before study treatment administration. The change from baseline in poststudy drug, post-bronchodilator FEV1 at Weeks 0 and 12 was analyzed using the ANCOVA model with treatment as a fixed effect and baseline value as a covariate. Post-bronchodilator spirometry measurements were performed 15-30 minutes after the administration of salbutamol (albuterol) 400 mcg via a metered dose inhaler (MDI) (spacer, where available). Placeboadjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at the specified time point for each arm respectively.

End point type

Secondary

End point timeframe

Week 0 (randomization) and Week 12.

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[52]	88 ^[53]	86 ^[54]	175 ^[55]	88 ^[56]
Units: litre(s)
arithmetic mean (standard error)
Week 0 (n=89, 85, 84, 173, 86)	0.0023 ( 0.0187 )	0.0143 ( 0.019 )	-0.0014 ( 0.019 )	-0.0022 ( 0.0154 )	-0.0153 ( 0.0189 )
Week 12 (n=76, 72, 71, 143, 69)	-0.0017 ( 0.0286 )	0.0626 ( 0.0292 )	0.0179 ( 0.0293 )	0.0121 ( 0.0237 )	0.025 ( 0.0296 )

Notes
[52] - Subjects who were evaluable for this measure.
[53] - Subjects who were evaluable for this measure.
[54] - Subjects who were evaluable for this measure.
[55] - Subjects who were evaluable for this measure.
[56] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FEV6 at Weeks 0 and 12

Top of page

End point title

Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FEV6 at Weeks 0 and 12 ^[57]

End point description

FEV6 is the maximal volume of air exhaled in the first 6 seconds of a forced expiration from a position of full inspiration. Trough FEV6 was obtained from spirometry, performed before study treatment administration. The change from baseline in post-study drug, post-bronchodilator FEV6 at Weeks 0 and 12 was analyzed using the ANCOVA model with treatment as a fixed effect and baseline value as a covariate. Post-bronchodilator spirometry measurements were performed 15-30 minutes after the administration of salbutamol (albuterol) 400 mcg via an MDI (spacer, where available). Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at the specified time point for each arm respectively.

End point type

Secondary

End point timeframe

Week 0 (randomization) and Week 12.

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[58]	88 ^[59]	86 ^[60]	175 ^[61]	88 ^[62]
Units: litre(s)
arithmetic mean (standard error)
Week 0 (n=89, 85, 84, 173, 86)	-0.0019 ( 0.0253 )	0.0082 ( 0.0257 )	-0.0025 ( 0.0258 )	-0.0014 ( 0.0208 )	-0.001 ( 0.0256 )
Week 12 (n=76, 72, 71, 143, 69)	0.0007 ( 0.0376 )	0.0576 ( 0.0383 )	0.0049 ( 0.0385 )	0.0088 ( 0.0311 )	0.0173 ( 0.0389 )

Notes
[58] - Subjects who were evaluable for this measure.
[59] - Subjects who were evaluable for this measure.
[60] - Subjects who were evaluable for this measure.
[61] - Subjects who were evaluable for this measure.
[62] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FVC at Weeks 0 and 12

Top of page

End point title

Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FVC at Weeks 0 and 12 ^[63]

End point description

FVC is the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Trough FVC was obtained from spirometry, performed before study treatment administration. The change from baseline in post-study drug, post-bronchodilator FVC at Weeks 0 and 12 was analyzed using the ANCOVA model with treatment as a fixed effect and baseline value as a covariate. Post-bronchodilator spirometry measurements were performed 15-30 minutes after the administration of salbutamol (albuterol) 400 mcg via an MDI (spacer, where available). Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at the specified time point for each arm respectively.

End point type

Secondary

End point timeframe

Week 0 (randomization) and Week 12.

Notes
[63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[64]	88 ^[65]	86 ^[66]	175 ^[67]	88 ^[68]
Units: litre(s)
arithmetic mean (standard error)
Week 0 (n=89, 85, 84, 173, 86)	0.03 ( 0.0335 )	0.0203 ( 0.0341 )	-0.0048 ( 0.0342 )	0.0204 ( 0.0276 )	0.0194 ( 0.0339 )
Week 12 (n=76, 72, 71, 143, 69)	0.005 ( 0.0441 )	0.0517 ( 0.045 )	-0.0044 ( 0.0452 )	0.0076 ( 0.0365 )	0.0242 ( 0.0457 )

Notes
[64] - Subjects who were evaluable for this measure.
[65] - Subjects who were evaluable for this measure.
[66] - Subjects who were evaluable for this measure.
[67] - Subjects who were evaluable for this measure.
[68] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator IC at Weeks 0 and 12

Top of page

End point title

Placebo-adjusted change from baseline in post-study drug, post-bronchodilator IC at Weeks 0 and 12 ^[69]

End point description

IC is the maximum volume of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Trough IC was obtained from spirometry, performed before study treatment administration. The change from baseline in post-study drug, post-bronchodilator IC at Weeks 0 and 12 was analyzed using the ANCOVA model with treatment as a fixed effect and baseline value as a covariate. Post-bronchodilator spirometry measurements were performed 15-30 minutes after the administration of salbutamol (albuterol) 400 mcg via an MDI (spacer, where available). Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at the specified time point for each arm respectively.

End point type

Secondary

End point timeframe

Week 0 (randomization) and Week 12.

Notes
[69] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[70]	88 ^[71]	86 ^[72]	175 ^[73]	88 ^[74]
Units: litre(s)
arithmetic mean (standard error)
Week 0 (n=89, 85, 84, 173, 87)	0.0284 ( 0.038 )	-0.0025 ( 0.0386 )	-0.0679 ( 0.0387 )	-0.0249 ( 0.0313 )	-0.0624 ( 0.0383 )
Week 12 (n=76, 72, 72, 144, 69)	0.0341 ( 0.0497 )	0.0071 ( 0.0506 )	-0.0187 ( 0.0506 )	-0.0345 ( 0.041 )	-0.0014 ( 0.0514 )

Notes
[70] - Subjects who were evaluable for this measure.
[71] - Subjects who were evaluable for this measure.
[72] - Subjects who were evaluable for this measure.
[73] - Subjects who were evaluable for this measure.
[74] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in chronic obstructive pulmonary disease (COPD) symptoms using The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptom (E-RS) Diary over 12 weeks of treatment

Top of page

End point title

Placebo-adjusted change from baseline in chronic obstructive pulmonary disease (COPD) symptoms using The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptom (E-RS) Diary over 12 weeks of treatment ^[75]

End point description

Subjects were required to evaluate the severity of their respiratory symptoms on a daily basis in the evening using an electronic diary by rating their respiratory symptoms according to how they felt during the preceding 24 hours (including the previous night). The E-RS was part of the EXACT and consisted of 11 out of 14 items relating to the 3 domains of breathlessness, cough and sputum, and chest symptoms. Each question (item) was summed to yield a total score which was converted to an EXACT total score on a 0 to 100 scale. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data for each score in each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[76]	88 ^[77]	86 ^[78]	175 ^[79]	88 ^[80]
Units: units on a scale
arithmetic mean (standard error)
Breathlessness score (n=89, 87, 86, 173, 88)	0.0079 ( 0.2149 )	-0.1272 ( 0.2177 )	0.1058 ( 0.2183 )	0.117 ( 0.1772 )	-0.0445 ( 0.2175 )
Cough & sputum score (n=89, 87, 86, 173, 88)	0.0323 ( 0.1208 )	-0.1372 ( 0.1227 )	-0.1408 ( 0.1229 )	-0.1029 ( 0.0997 )	-0.307 ( 0.1225 )
Chest symptoms score (n=89, 87, 86, 173, 88)	-0.0549 ( 0.1375 )	-0.1434 ( 0.1395 )	0.0615 ( 0.1398 )	-0.0181 ( 0.1135 )	-0.0599 ( 0.1393 )
Total score (n=89, 87, 86, 173, 88)	-0.0326 ( 0.4177 )	-0.3896 ( 0.4234 )	0.0266 ( 0.4244 )	-0.003 ( 0.3447 )	-0.4013 ( 0.4228 )

Notes
[76] - Subjects who were evaluable for this measure.
[77] - Subjects who were evaluable for this measure.
[78] - Subjects who were evaluable for this measure.
[79] - Subjects who were evaluable for this measure.
[80] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in Chronic Respiratory Questionnaire - Self Administered Standard (CRQ-SAS) at Weeks 2, 6, 10 and 12 - Dyspnea domain

Top of page

End point title

Placebo-adjusted change from baseline in Chronic Respiratory Questionnaire - Self Administered Standard (CRQ-SAS) at Weeks 2, 6, 10 and 12 - Dyspnea domain ^[81]

End point description

The CRQ-SAS questionnaire is a COPD specific measure of quality of life. It includes 20 items measuring 4 domains: Dyspnea (5 items), Fatigue (4 items), Emotional Function (7 Items), and Mastery (4 items). Subjects were asked to record their answers on a 7-point scale (1 = maximum impairment to 7 = no impairment). The scores for each question of each domain were simply added together and divided by the number of questions in the domain. Due to the scaling of the responses on the CRQ-SAS, an increase in scoring from baseline would show a therapeutic benefit of the medication. Dyspnea domain score ranged from 1 to 7, where higher score indicated lesser impairment. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[81] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, no data for placebo can be obtained.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[82]	88 ^[83]	86 ^[84]	175 ^[85]	88 ^[86]
Units: units on a scale
arithmetic mean (standard error)
Week 2 (n=80, 74, 79, 158, 74)	0.0434 ( 0.1013 )	0.0114 ( 0.1042 )	0.0184 ( 0.102 )	-0.0277 ( 0.0828 )	-0.1151 ( 0.1036 )
Week 6 (n=77, 66, 74, 148, 70)	0.1235 ( 0.1122 )	0.0382 ( 0.117 )	0.0381 ( 0.1138 )	0.0167 ( 0.0922 )	-0.0685 ( 0.1152 )
Week 10 (n-73, 65, 72, 136, 59)	0.0764 ( 0.1196 )	0.0364 ( 0.1239 )	-0.1663 ( 0.1206 )	-0.0454 ( 0.0986 )	-0.1943 ( 0.1257 )
Week 12 (n=72, 63, 67, 139, 61)	-0.0227 ( 0.1259 )	-0.0504 ( 0.131 )	-0.0171 ( 0.1282 )	-0.0586 ( 0.1034 )	0.0261 ( 0.1316 )

Notes
[82] - Subjects who were evaluable for this measure.
[83] - Subjects who were evaluable for this measure.
[84] - Subjects who were evaluable for this measure.
[85] - Subjects who were evaluable for this measure.
[86] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Fatigue domain

Top of page

End point title

Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Fatigue domain ^[87]

End point description

The CRQ-SAS questionnaire is a COPD specific measure of quality of life. It includes 20 items measuring 4 domains: Dyspnea (5 items), Fatigue (4 items), Emotional Function (7 Items), and Mastery (4 items). Subjects were asked to record their answers on a 7-point scale (1 = maximum impairment to 7 = no impairment). The scores for each question of each domain were simply added together and divided by the number of questions in the domain. An increase in scoring from baseline would show a therapeutic benefit of the medication. Fatigue domain score ranged from 1 to 7, where higher score indicated less impairment. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[87] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[88]	88 ^[89]	86 ^[90]	175 ^[91]	88 ^[92]
Units: units on a scale
arithmetic mean (standard error)
Week 2 (n=87, 83, 83, 171, 83)	0.0162 ( 0.0891 )	0.068 ( 0.0906 )	0.04 ( 0.0906 )	-0.086 ( 0.0733 )	-0.0199 ( 0.0905 )
Week 6 (n=83, 78, 80, 158, 79)	0.0224 ( 0.1073 )	0.0358 ( 0.1094 )	-0.0018 ( 0.1087 )	-0.0891 ( 0.0887 )	-0.0155 ( 0.1089 )
Week 10 (n=79, 73, 76, 147, 70)	-0.0355 ( 0.1088 )	0.0362 ( 0.1114 )	-0.157 ( 0.1102 )	-0.134 ( 0.0902 )	-0.0726 ( 0.1123 )
Week 12 (n=78, 73, 74, 147, 69)	-0.0448 ( 0.1157 )	0.0199 ( 0.1182 )	-0.0368 ( 0.1175 )	-0.136 ( 0.0958 )	-0.0037 ( 0.1196 )

Notes
[88] - Subjects who were evaluable for this measure.
[89] - Subjects who were evaluable for this measure.
[90] - Subjects who were evaluable for this measure.
[91] - Subjects who were evaluable for this measure.
[92] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Emotional Function domain

Top of page

End point title

Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Emotional Function domain ^[93]

End point description

The CRQ-SAS questionnaire is a COPD specific measure of quality of life. It includes 20 items measuring 4 domains: Dyspnea (5 items), Fatigue (4 items), Emotional Function (7 Items), and Mastery (4 items). Subjects were asked to record their answers on a 7-point scale (1 = maximum impairment to 7 = no impairment). The scores for each question of each domain were simply added together and divided by the number of questions in the domain. An increase in scoring from baseline would show a therapeutic benefit of the medication. Emotional function domain score ranged from 1 to 7, where higher score indicated lesser impairment. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[93] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[94]	88 ^[95]	86 ^[96]	175 ^[97]	88 ^[98]
Units: units on a scale
arithmetic mean (standard error)
Week 2 (n=87, 83, 83, 171, 83)	0.0532 ( 0.0796 )	0.0655 ( 0.0812 )	0.0268 ( 0.0809 )	-0.0247 ( 0.0654 )	-0.0184 ( 0.0808 )
Week 6 (n=83, 78, 80, 158, 79)	0.0617 ( 0.0964 )	-0.0007 ( 0.0985 )	-0.0927 ( 0.0976 )	-0.0592 ( 0.0796 )	-0.0063 ( 0.0978 )
Week 10 (n=79, 74, 77, 147, 70)	-0.0633 ( 0.0974 )	-0.0461 ( 0.0996 )	-0.1031 ( 0.0984 )	-0.1441 ( 0.0806 )	-0.1314 ( 0.1005 )
Week 12 (n=78, 73, 74, 147, 69)	-0.0792 ( 0.1038 )	-0.0561 ( 0.1062 )	-0.1004 ( 0.1053 )	-0.1281 ( 0.0859 )	-0.035 ( 0.1072 )

Notes
[94] - Subjects who were evaluable for this measure.
[95] - Subjects who were evaluable for this measure.
[96] - Subjects who were evaluable for this measure.
[97] - Subjects who were evaluable for this measure.
[98] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Mastery domain

Top of page

End point title

Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Mastery domain ^[99]

End point description

The CRQ-SAS questionnaire is a COPD specific measure of quality of life. It includes 20 items measuring 4 domains: Dyspnea (5 items), Fatigue (4 items), Emotional Function (7 Items), and Mastery (4 items). Subjects were asked to record their answers on a 7-point scale (1 = maximum impairment to 7 = no impairment). The scores for each question of each domain were simply added together and divided by the number of questions in the domain. An increase in scoring from baseline would show a therapeutic benefit of the medication. Mastery domain score ranged from 1 to 7, where higher score indicated lesser impairment. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10 and 12.

Notes
[99] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[100]	88 ^[101]	86 ^[102]	175 ^[103]	88 ^[104]
Units: units on a scale
arithmetic mean (standard error)
Week 2 (n=87, 83, 83, 171, 83)	0.1131 ( 0.0996 )	0.1527 ( 0.1014 )	-0.0314 ( 0.1012 )	0.0418 ( 0.0818 )	0.0242 ( 0.1011 )
Week 6 (n=83, 78, 80, 158, 79)	-0.027 ( 0.1123 )	0.0832 ( 0.1146 )	-0.0823 ( 0.1138 )	-0.0822 ( 0.0927 )	-0.0767 ( 0.114 )
Week 10 (n=79, 73, 76, 147, 70)	-0.0142 ( 0.1156 )	-0.1039 ( 0.1184 )	-0.3125 ( 0.1171 )	-0.0777 ( 0.0957 )	-0.1277 ( 0.1192 )
Week 12 (n=78, 73, 74, 147, 69)	-0.1963 ( 0.1235 )	-0.0387 ( 0.1263 )	-0.3888 ( 0.1254 )	-0.2103 ( 0.1021 )	-0.2243 ( 0.1275 )

Notes
[100] - Subjects who were evaluable for this measure.
[101] - Subjects who were evaluable for this measure.
[102] - Subjects who were evaluable for this measure.
[103] - Subjects who were evaluable for this measure.
[104] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Frequency of responses in the Patient Global Impression of Change at Week 12

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End point title

Frequency of responses in the Patient Global Impression of Change at Week 12

End point description

The subject's overall subjective rating of any change in their COPD symptoms since the start of the study was captured in the Patient Global Impression of Change which was completed by subjects at Week 12. Responses consisted of very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse. The percentage of subjects with response based on the Patient Global Impression of Change were presented. All subjects in the FAS who had available data for this endpoint were included in this summary.

End point type

Secondary

End point timeframe

Week 12.

End point values	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	158	79	73	74	147	69
Units: Percentage of subjects
number (not applicable)
Very much improved	4.4	7.6	0	2.7	2.7	4.3
Much improved	12.7	17.7	23.3	21.6	21.1	23.2
Minimally improved	48.1	36.7	42.5	29.7	36.1	42
No change	31.6	32.9	31.5	33.8	31.3	27.5
Minimally worse	3.2	2.5	1.4	10.8	6.8	2.9
Much worse	0	2.5	1.4	1.4	2	0
Very much worse	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Frequency of responses in the Clinician Global Impression of Change at Week 12

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End point title

Frequency of responses in the Clinician Global Impression of Change at Week 12

End point description

The investigator’s overall rating of the change in the subject's COPD symptoms since the start of the study was captured in the Clinician Global Impression of Change which was completed by the investigator at Week 12. Responses consisted of very much improved, much improved, minimally improved, no change, minimally worse, much worse, and very much worse. The percentage of subjects with response based on Clinician Global Impression of Change were presented. All subjects in the FAS who had available data for this endpoint were included in this summary.

End point type

Secondary

End point timeframe

Week 12.

End point values	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	157	78	73	74	145	69
Units: Percentage of subjects
number (not applicable)
Very much improved	2.5	1.3	0	5.4	4.1	4.3
Much improved	14.6	21.8	21.9	18.9	18.6	13
Minimally improved	44.6	39.7	34.2	27	36.6	37.7
No change	36.3	34.6	38.4	37.8	31	42
Minimally worse	1.9	2.6	5.5	9.5	9	2.9
Much worse	0	0	0	1.4	0.7	0
Very much worse	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Placebo-adjusted ratio in number of weekly puffs of rescue bronchodilator use (per daily diary)

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End point title

Placebo-adjusted ratio in number of weekly puffs of rescue bronchodilator use (per daily diary) ^[105]

End point description

Subjects recorded in the daily diary the total number of puffs of any short acting bronchodilator (salbutamol) medication taken in the past 24 hours for any reason during the evening. The log of the number of weekly puffs of rescue bronchodilator use was analyzed by the longitudinal mixed effects model. Placebo-adjusted data was reported. Analysis was done on the evaluable subjects in the FAS.

End point type

Secondary

End point timeframe

Baseline up to Week 12.

Notes
[105] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	80	75	75	159	77
Units: Ratio
arithmetic mean (standard error)	0.959 ( 0.0757 )	0.9661 ( 0.0786 )	0.9264 ( 0.0747 )	0.9355 ( 0.0612 )	0.8375 ( 0.0674 )

No statistical analyses for this end point

Secondary: Change from baseline (Baseline Dyspnea Index [BDI]) in dyspnea (Transition Dyspnea Index [TDI]) at Weeks 2, 6, 10 and 12

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End point title

Change from baseline (Baseline Dyspnea Index [BDI]) in dyspnea (Transition Dyspnea Index [TDI]) at Weeks 2, 6, 10 and 12

End point description

BDI: 24-item questionnaire to assess baseline dyspnea in 3 domains, functional impairment; magnitude of task; magnitude of effort. Each item rated on 5-point scale: 0 (very severe), 4 (no impairment). BDI total score range: 0 to 12, lower score=more severe dyspnea. TDI: 24-item questionnaire to measure changes in dyspnea severity from baseline in same 3 domains, as in BDI. Each item rated on 7-point scale: -3 (major deterioration) to 3 (major improvement). TDI total score range: -9 to 9, lower score=more deterioration. BDI/TDI total scores were obtained by adding scores for each of 3 domains. Analysis was done on the FAS. "n" signifies subjects with available data at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Baseline; Weeks 2, 6, 10, and 12.

End point values	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	176 ^[106]	89 ^[107]	88 ^[108]	86 ^[109]	175 ^[110]	88 ^[111]
Units: units on a scale
arithmetic mean (standard error)
Week 2 (n=171, 88, 83, 83, 171, 84)	0.9237 ( 0.153 )	0.9546 ( 0.2132 )	1.0733 ( 0.22 )	0.9396 ( 0.2195 )	0.7365 ( 0.153 )	1.1024 ( 0.2178 )
Week 6 (n=165, 84, 78, 80, 158, 79)	1.3651 ( 0.1828 )	1.3047 ( 0.2558 )	1.6243 ( 0.2653 )	1.4025 ( 0.2625 )	0.9158 ( 0.1857 )	1.7519 ( 0.2628 )
Week 10 (n=160, 79, 74, 77, 147, 70)	1.4391 ( 0.2019 )	1.8145 ( 0.2852 )	1.3107 ( 0.2951 )	1.1386 ( 0.2905 )	0.9987 ( 0.208 )	1.8776 ( 0.2985 )
Week 12 (n=158, 77, 73, 74, 147, 69)	1.9102 ( 0.2092 )	2.269 ( 0.2966 )	1.592 ( 0.3061 )	1.5267 ( 0.3028 )	1.2234 ( 0.2153 )	1.6961 ( 0.3105 )

Notes
[106] - Subjects who were evaluable for this measure.
[107] - Subjects who were evaluable for this measure.
[108] - Subjects who were evaluable for this measure.
[109] - Subjects who were evaluable for this measure.
[110] - Subjects who were evaluable for this measure.
[111] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Percentage of subjects with post-baseline electrocardiogram (ECG) measurements meeting categorical summarization criteria

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End point title

Percentage of subjects with post-baseline electrocardiogram (ECG) measurements meeting categorical summarization criteria

End point description

Triplicate 12-lead ECG measurements (each recording separated by 2 to 4 minutes) were performed and the average was calculated. The time from ECG Q wave to the end of the T wave corresponding to electrical systole (QT) was corrected for heart rate (QTc). QTc using Fridericia’s formula (QTcF) was calculated. Subjects with maximum increase from baseline of 30 to less than (<) 60 milliseconds (msec) and more than or equal to (>=) 60 msec for QTcF were summarized, as were those with post-baseline absolute (abs) QT values of >=500 msec. Analysis was done on the subjects in the safety analysis set (all randomized subjects who had received at least 1 dose of study drug, regardless of whether they had efficacy data) who had post-baseline ECG data. "n" signifies subjects with available data for each measurement at each time point for each arm respectively.

End point type

Secondary

End point timeframe

Weeks 2, 6, 10 and 12; follow-up (Week 14).

End point values	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	180 ^[112]	90 ^[113]	89 ^[114]	88 ^[115]	180 ^[116]	89 ^[117]
Units: Percentage of subjects
number (not applicable)
QTcF: 30- <60 msec, Week 2 (n=175,89,86,85,176,86)	1.1	2.2	1.2	1.2	6.3	2.3
QTcF: 30- <60 msec, Week 6 (n=169,85,81,81,162,80)	1.8	0	0	3.7	1.9	0
QTcF: 30- <60 msec, Week 10(n=164,79,77,79,152,70)	1.2	1.3	0	5.1	7.2	2.9
QTcF: 30 - <60 msec, Week12(n=162,79,76,76,150,70)	1.2	1.3	2.6	3.9	3.3	5.7
QTcF: 30 - <60 msec, Week14(n=162,79,76,75,152,70)	0.6	1.3	2.6	2.7	0.7	1.4
QTcF: >=60 msec, Week 2(n=175,89,86,85,176,86)	0	0	0	0	0	0
QTcF: >=60 msec, Week 6(n=169,85,81,81,162,80)	0	0	0	0	0	0
QTcF: >=60 msec, Week 10(n=164,79,77,79,152,70)	0	0	0	0	0	0
QTcF: >=60 msec, Week 12(n=162,79,76,76,150,70)	0	0	0	0	0	0
QTcF: >=60 msec, Week 14(n=162,79,76,75,152,70)	0	0	0	0	0	0
Abs QT >=500 msec, Week 2(n=175,89,86,85,178,86)	0	0	0	0	0	0
Abs QT >=500 msec, Week 6(n=169,85,81,82,165,80)	0	0	0	0	0	0
Abs QT >=500 msec, Week 10(n=164,81,77,79,154,71)	0	1.2	0	0	0	0
Abs QT >=500 msec, Week 12(n=162,80,76,76,154,70)	0	0	0	0	0	0
Abs QT >=500 msec, Week 14(n=162,79,76,75,154,70)	0	0	0	0	0	0

Notes
[112] - Subjects who were evaluable for this measure.
[113] - Subjects who were evaluable for this measure.
[114] - Subjects who were evaluable for this measure.
[115] - Subjects who were evaluable for this measure.
[116] - Subjects who were evaluable for this measure.
[117] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Secondary: Number of subjects with changes from baseline in vital signs values which met criteria for categorical summarization

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End point title

Number of subjects with changes from baseline in vital signs values which met criteria for categorical summarization

End point description

Subjects with supine systolic blood pressure (BP) <90 millimeters of mercury (mmHg), maximum increase and decrease from baseline supine systolic BP of >=30 mmHg, supine diastolic BP <50 mmHg, and maximum increase and decrease from baseline supine diastolic BP >=20 mmHg at any time post dose were summarized. Subjects with supine pulse rate (PR) <40 or >120 beats per minute (bpm) were also summarized. Analysis was done on the subjects in the safety analysis set (all subjects randomized who had received at least 1 dose of study drug, regardless of whether they had efficacy data) who had available vital signs data.

End point type

Secondary

End point timeframe

Baseline; Week 2 up to Week 14.

End point values	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	179	90	89	88	182	89
Units: Subjects
Systolic BP <90 mmHg	1	0	0	0	0	0
Decrease from baseline systolic BP >=30 mmHg	8	4	4	5	9	8
Increase from baseline systolic BP >=30 mmHg	4	2	2	1	9	1
Diastolic BP <50 mmHg	0	0	0	0	0	1
Decrease from baseline diastolic BP >=20 mmHg	10	5	4	3	12	5
Increase from baseline diastolic BP >=20 mmHg	6	3	2	5	8	5
Supine PR <40 bpm	0	0	0	0	0	0
Supine PR >120 bpm	0	0	0	2	1	0

No statistical analyses for this end point

Secondary: Number of subjects with laboratory test abnormalities

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End point title

Number of subjects with laboratory test abnormalities

End point description

Number of subjects with laboratory test abnormalities without regard to baseline abnormality. Laboratory test parameters included hematology, liver function, renal function, electrolytes, clinical chemistry, and urinalysis (dipstick and microscopy). Analysis was done on subjects in the safety analysis set (all subjects randomized who had received at least 1 dose of study drug, regardless of whether they had efficacy data) who had post-baseline laboratory data.

End point type

Secondary

End point timeframe

Baseline; Week 2 up to Week 14.

End point values	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	180	90	89	88	182	88
Units: Subjects	150	79	66	76	144	68

No statistical analyses for this end point

Secondary: Number of subjects with treatment-emergent adverse events (AEs)

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End point title

Number of subjects with treatment-emergent adverse events (AEs)

End point description

Number of subjects with all causality treatment-emergent adverse events. Analysis was done on the safety analysis set which included all subjects randomized who had received at least 1 dose of study drug, regardless of whether they had efficacy data.

End point type

Secondary

End point timeframe

Baseline up to Week 14.

End point values	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	181	90	91	88	182	89
Units: Subjects	72	41	43	45	103	46

No statistical analyses for this end point

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FVC at Weeks 0 and 12

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End point title

Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FVC at Weeks 0 and 12 ^[118]

End point description

FVC is the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Trough FVC was obtained from spirometry, performed before study treatment administration. The change from baseline in post-study drug, pre-bronchodilator FVC at Weeks 0 and 12 was analyzed using the ANCOVA model with treatment as a fixed effect and baseline value as a covariate. Post-study drug spirometry was performed 15-30 minutes after administration of study drug at the Weeks 0 and 12 visits. Placebo-adjusted data was reported. Analysis was done on the FAS. "n" signifies subjects with available data at the specified time point for each arm respectively.

End point type

Secondary

End point timeframe

Week 0 (randomization) and Week 12.

Notes
[118] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Placebo-adjusted estimates are reported. As such, there is no data for the placebo arm.

End point values	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Number of subjects analysed	89 ^[119]	88 ^[120]	86 ^[121]	175 ^[122]	88 ^[123]
Units: litre(s)
arithmetic mean (standard error)
Week 0 (n=89, 85, 85, 175, 87)	0.0467 ( 0.0259 )	0.0159 ( 0.0264 )	-0.0127 ( 0.0264 )	0.0221 ( 0.0213 )	0.0032 ( 0.0262 )
Week 12 (n=77, 72, 72, 146, 69)	-0.0051 ( 0.0237 )	-0.0014 ( 0.0243 )	-0.0289 ( 0.0243 )	-0.0059 ( 0.0196 )	-0.0159 ( 0.0247 )

Notes
[119] - Subjects who were evaluable for this measure.
[120] - Subjects who were evaluable for this measure.
[121] - Subjects who were evaluable for this measure.
[122] - Subjects who were evaluable for this measure.
[123] - Subjects who were evaluable for this measure.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 28 days after last study drug administration.

Adverse event reporting additional description

All treated subjects were analyzed for adverse events (AEs). The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to PH-797804 tablet plus tiotropium bromide 18 microgram (mcg) orally once daily for 12 weeks.

Reporting group title

PH-797804 0.25 mg

Reporting group description

Subjects received PH-797804 0.25 milligram (mg) plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 1 mg

Reporting group description

Subjects received PH-797804 1 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 3 mg

Reporting group description

Subjects received PH-797804 3 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 6 mg

Reporting group description

Subjects received PH-797804 6 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Reporting group title

PH-797804 10 mg

Reporting group description

Subjects received PH-797804 10 mg plus tiotropium bromide 18 mcg orally once daily for 12 weeks.

Serious adverse events	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 181 (3.31%)	3 / 90 (3.33%)	2 / 91 (2.20%)	3 / 88 (3.41%)	6 / 182 (3.30%)	3 / 89 (3.37%)
number of deaths (all causes)	2	0	0	0	2	0
number of deaths resulting from adverse events		0	0	0		0
Injury, poisoning and procedural complications
Ilium fracture
subjects affected / exposed	0 / 181 (0.00%)	1 / 90 (1.11%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 181 (0.00%)	1 / 90 (1.11%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	1 / 181 (0.55%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	1 / 182 (0.55%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 181 (0.55%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	0 / 91 (0.00%)	2 / 88 (2.27%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 181 (0.55%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	1 / 182 (0.55%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Tachycardia
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	1 / 182 (0.55%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Convulsion
subjects affected / exposed	1 / 181 (0.55%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	1 / 182 (0.55%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Duodenal ulcer
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	1 / 91 (1.10%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 181 (0.00%)	1 / 90 (1.11%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	1 / 181 (0.55%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 181 (0.55%)	0 / 90 (0.00%)	1 / 91 (1.10%)	1 / 88 (1.14%)	3 / 182 (1.65%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchopneumonia
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	0 / 91 (0.00%)	0 / 88 (0.00%)	0 / 182 (0.00%)	1 / 89 (1.12%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	1 / 91 (1.10%)	0 / 88 (0.00%)	0 / 182 (0.00%)	0 / 89 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	PH-797804 0.25 mg	PH-797804 1 mg	PH-797804 3 mg	PH-797804 6 mg	PH-797804 10 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	28 / 181 (15.47%)	20 / 90 (22.22%)	16 / 91 (17.58%)	16 / 88 (18.18%)	55 / 182 (30.22%)	17 / 89 (19.10%)
Gastrointestinal disorders
Dry mouth
subjects affected / exposed	0 / 181 (0.00%)	0 / 90 (0.00%)	0 / 91 (0.00%)	3 / 88 (3.41%)	10 / 182 (5.49%)	1 / 89 (1.12%)
occurrences all number	0	0	0	3	10	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	14 / 181 (7.73%)	13 / 90 (14.44%)	6 / 91 (6.59%)	4 / 88 (4.55%)	26 / 182 (14.29%)	10 / 89 (11.24%)
occurrences all number	15	13	6	5	31	10
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	6 / 181 (3.31%)	1 / 90 (1.11%)	2 / 91 (2.20%)	5 / 88 (5.68%)	8 / 182 (4.40%)	5 / 89 (5.62%)
occurrences all number	6	1	2	5	8	7
Infections and infestations
Nasopharyngitis
subjects affected / exposed	11 / 181 (6.08%)	7 / 90 (7.78%)	10 / 91 (10.99%)	10 / 88 (11.36%)	24 / 182 (13.19%)	4 / 89 (4.49%)
occurrences all number	12	7	11	10	30	6

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Were there any global substantial amendments to the protocol? Yes

27 Nov 2012

Safety-related amendments made: - correction of protocol inconsistency in referring to GOLD updates (should refer to GOLD update 2010 instead of 2009). - updated inclusion criterion regarding female of non-childbearing potential. - updated an exclusion criterion to clarify that sites were allowed to repeat screening lab tests once if they suspected abnormal results were anomalous. - updated an exclusion criterion to clarify that abstinence from intercourse was to be during the study period and not just the ovulation period. - updates to Prohibited Medications section: sponsor would review concomitant medications on a weekly basis as part of data safety review. Also, it was clarified that subjects had to be on tiotropium bromide as background theray for 1 month prior to screening in order to be eligible and were not to be consented to be started on tiotropium bromide solely for the purpose of participating in the study. - Procedures were restructured where applicable to specify that procedures were to be completed from the least to the most invasive. Eg, electrocardiogram (ECG) was to be performed before vitals and blood draw for labs. - updates to Randomization Visit procedures to reflect that salbutamol was not to be taken daily and also clarifications where applicable on how salbutamol was to be administered. - addition of text to clarify that full physical examination included vital sign and blood pressure measurements. - updates to ensure sites knew that weekly phone calls to subjects were to start after Screening Visit. - updates to clarify that any subject with clinically significant finding on ECG was to have appropriate follow-up. - addition of text to clarify details of COPD symptoms, exacerbations, and rescue bronchodilator usage analyses. - clarified that unblinded safety review by Internal Review Committee was to be conducted after approximately 1/3 and 2/3 of subjects have been randomized. - tuberculosis testing algorithm diagram updated.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Subject disposition and baseline characteristics are provided for treated subjects only.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Placebo-corrected change from baseline in trough (pre-treatment and pre-bronchodilator) FEV1 at Week 12

Primary: Placebo-corrected change from baseline in trough (pre-treatment and pre-bronchodilator) FEV1 at Week 12

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator FEV1 at Weeks 2, 6, and 10

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator FEV1 at Weeks 2, 6, and 10

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator forced expiratory volume in 6 seconds (FEV6) at Weeks 2, 6, 10 and 12

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator forced expiratory volume in 6 seconds (FEV6) at Weeks 2, 6, 10 and 12

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator forced vital capacity (FVC) at Weeks 2, 6, 10 and 12

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator forced vital capacity (FVC) at Weeks 2, 6, 10 and 12

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator inspiratory capacity (IC) at Weeks 2, 6, 10 and 12

Secondary: Placebo-adjusted change from baseline in trough, pre-bronchodilator inspiratory capacity (IC) at Weeks 2, 6, 10 and 12

Secondary: Average placebo-adjusted change from baseline in trough, pre-bronchodilator FEV1, FEV6, FVC, and IC over 12 weeks of treatment

Secondary: Average placebo-adjusted change from baseline in trough, pre-bronchodilator FEV1, FEV6, FVC, and IC over 12 weeks of treatment

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FEV1 at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FEV1 at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FEV6 at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FEV6 at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator IC at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator IC at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FEV1 at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FEV1 at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FEV6 at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FEV6 at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FVC at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator FVC at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator IC at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, post-bronchodilator IC at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in chronic obstructive pulmonary disease (COPD) symptoms using The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptom (E-RS) Diary over 12 weeks of treatment

Secondary: Placebo-adjusted change from baseline in chronic obstructive pulmonary disease (COPD) symptoms using The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptom (E-RS) Diary over 12 weeks of treatment

Secondary: Placebo-adjusted change from baseline in Chronic Respiratory Questionnaire - Self Administered Standard (CRQ-SAS) at Weeks 2, 6, 10 and 12 - Dyspnea domain

Secondary: Placebo-adjusted change from baseline in Chronic Respiratory Questionnaire - Self Administered Standard (CRQ-SAS) at Weeks 2, 6, 10 and 12 - Dyspnea domain

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Fatigue domain

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Fatigue domain

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Emotional Function domain

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Emotional Function domain

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Mastery domain

Secondary: Placebo-adjusted change from baseline in CRQ-SAS at Weeks 2, 6, 10 and 12 - Mastery domain

Secondary: Frequency of responses in the Patient Global Impression of Change at Week 12

Secondary: Frequency of responses in the Patient Global Impression of Change at Week 12

Secondary: Frequency of responses in the Clinician Global Impression of Change at Week 12

Secondary: Frequency of responses in the Clinician Global Impression of Change at Week 12

Secondary: Placebo-adjusted ratio in number of weekly puffs of rescue bronchodilator use (per daily diary)

Secondary: Placebo-adjusted ratio in number of weekly puffs of rescue bronchodilator use (per daily diary)

Secondary: Change from baseline (Baseline Dyspnea Index [BDI]) in dyspnea (Transition Dyspnea Index [TDI]) at Weeks 2, 6, 10 and 12

Secondary: Change from baseline (Baseline Dyspnea Index [BDI]) in dyspnea (Transition Dyspnea Index [TDI]) at Weeks 2, 6, 10 and 12

Secondary: Percentage of subjects with post-baseline electrocardiogram (ECG) measurements meeting categorical summarization criteria

Secondary: Percentage of subjects with post-baseline electrocardiogram (ECG) measurements meeting categorical summarization criteria

Secondary: Number of subjects with changes from baseline in vital signs values which met criteria for categorical summarization

Secondary: Number of subjects with changes from baseline in vital signs values which met criteria for categorical summarization

Secondary: Number of subjects with laboratory test abnormalities

Secondary: Number of subjects with laboratory test abnormalities

Secondary: Number of subjects with treatment-emergent adverse events (AEs)

Secondary: Number of subjects with treatment-emergent adverse events (AEs)

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FVC at Weeks 0 and 12

Secondary: Placebo-adjusted change from baseline in post-study drug, pre-bronchodilator FVC at Weeks 0 and 12

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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